Gene targeting provides the means for creating mice with designed modifications in any chosen gene. This technology permits the evaluation of the function of any gene in the living mouse and the systematic dissection of the most complex biological processes. It can be used to generate animal models of any human disease in order to study its pathology at a level of detail not feasible in human patients, and for the development of new more effective therapies that are based on a molecular-genetic understanding of the disease. This grant will continue to emphasize the development of gene-targeting-based technologies for the study of human biology and medicine. The particular projects that will be pursued in this grant proposal through the use of gene targeting include: To determine the roles of Hox genes in building simple neural circuits, particularly those involving the facial and lumbar motor nuclei;and to model the human sarcomas, alveolar rhabdomyosarcoma, synovial sarcoma, and Ewing's sarcoma in the mouse. These are very aggressive cancers that principally affect children, adolescents, and young adults and do not respond satisfactorily to the current common therapeutic modalities of surgery, radiation, and chemotherapy. They are prime candidates for the development of new, more effective therapies based on an understanding of the molecular etiology responsible for the progression of each of these cancers.